Effects of cytochalasin B on the intrcellular bactericidal activity of human neutrophils. Cytochalasin B (CB) is known to have some inhibitory effects on cytokinesis, single-cell movement, bacterial uptake by phagocytes, and many other processes. The effects of CB on intraleukocytic bactericidal activities in human leukocytes were studied, and the results were summarized as follows. (i) CB inhibited the early stage of the intracellular bactericidal activity of human leukocytes against Streptococcus pyogenes D58 (group A). The effect was rapidly eliminated by rinsing the CB solution. (ii) In the late stage of the intracellular bactericidal process, however, CB possessed no effect against S. pyogenes D58 (group A) and Staphylococcus aureus 209P. (iii) CB also inhibited the translocation of myeloperoxidase granules to the phagosomes of human neutrophils.


Comparison of sisomicin and gentamicin in bacteriuric patients with underlying diseases of the urinary tract. Sisomicin and gentamicin (2 mg/kg) were administered in a random fashion to patients with bacteriuria superimposed on abnormalities of the urinary tract. Cure was achieved in a similar number of patients in both groups, but superinfection and reinfection with resistant microorganisms was more frequent in patients receiving gentamicin. Untoward side effects were not frequent in this series, especially if the serious underlying urological disease of most patients is taken into consideration. The susceptibility of the causative pathogens to the antibiotic administered and the severity of the underlying disease were the most important factors in the outcome.


Bacteriocin of a group B streptococcus: partial purification and characterization. The production of bacteriocin-like inhibition by two of 135 strains of group B streptococci was demonstrated during the growth of these organisms on solid nutrient media. Although a variety of gram-positive organisms was susceptible, none of a wide range of different gram-negative strains was inhibited. The active substance produced by one of these strains was extracted from cultures grown on solid media (Todd-Hewitt agar) and was shown to be bactericidal in action. This bacteriocin (streptocin B(1)) was partially purified by ammonium sulfate precipitation followed by gel filtration and ion-exchange chromatography. Production of the bacteriocin was repressed by addition of certain fermentable carbohydrates to the basic medium and enhanced by the addition of yeast extract. The bacteriocin was shown to exist in two distinct and interconvertible physical forms: a basic unit of molecular weight 10,000 and an aggregate having a molecular weight of over 200,000. The bacteriocin was inactivated by proteolytic enzymes and, although labile in alkali, it was stable to boiling in mild acids.


Herpesvirus hominis infection in newborn mice: treatment with interferon inducer polyinosinic-polycytidylic acid. Intranasal inoculation of newborn mice with Herpesvirus hominis (HVH) type 2 provides a model for disseminated herpesvirus infections of human newborn infants. Treatment of this experimental infection with polyinosinic-polycytidylic acid [poly(I:C)] significantly increased the mean survival time and markedly altered the pathogenesis of the infection. No significant protection against final mortality was observed. Poly(I:C) therapy completely inhibited detectable viral replication in all target organs tested except the brain. In the brain there was a 2-day delay in the onset of viral replication in treated animals, which correlated with the 1- to 2-day increase in mean survival time. In general, the control of HVH replication occurred in those target organs in which poly(I:C)-induced interferon was detectable. The failure of poly(I:C) to alter the final mortality of newborn mice infected with HVH appears to be primarily due to the lack of sufficient levels of interferon induced in brain tissue and the failure to prevent viral replication in this critical target organ.


Improved methods for production, isolation, and assay of two new chlorisoxazoline amino acid antitumor antimetabolites: U-42, 126 and U43, 795. Improved fermentation and isolation procedures for antitumor antimetabolites U-42,126 and U-43,795 increased drug yields 30-fold. The sensitivity limit of a newly developed assay is 0.03 mug of U-42,126 and 2.0 mug of U-43,795 per ml. The in vitro antimicrobial effect of both drugs was antagonized by histidine.


Antibiotic G418, a new micrommomospora-produced aminglycoside with activity apainst protozoa and helminths: antiparasitic activity. Antibiotic G-418 was shown to be superior to paromomycin and metronidazole in cecal amoebiasis. Of particular interest was the high degree of activity seen with a relatively short treatment at low levels. Although the antibiotic was trichomonacidal in vitro at low levels, in vivo results indicated that at levels tested the antibiotic did not always affect cures. The antibiotic appears to have promise as an anticestode agent, being more active than paromomycin against Hymenolepis nana and active as a single oral dose at low levels against Taenia spp.


Renal and biliary disposition of dapsone in the dog. Dapsone (4,4'-diaminodiphenylsulfone [DDS]) was administered intravenously to anesthetized dogs; urine was collected, heparinized venous blood was obtained, and bile was collected from some of the dogs. A constant infusion of inulin was maintained, and isosmotic or hypoosmotic fluids were administered. Dogs were studied under conditions of standardized, increased or decreased urine flow, and before and after plasmapheresis. Plasma, urine, and bile samples were analyzed for DDS and DDS conjugates; the degree of binding of DDS by plasma proteins was also determined. The renal clearances of inulin and DDS were calculated. No monoacetyldapsone (MADDS) was detected in the plasma, and only negligible quantities were found in the urine. Small quantities of DDS and DDS conjugates were detected in the bile in 4 h following the dose. Between 10 and 30% of the administered drug could be identified as DDS plus DDS conjugates in the urine in 8 h after the dose. Renal clearance of unbound DDS was proportional to the urine flow rate, and the clearance ratio of DDS to inulin approached the same maximal value as that for urea. Although the rate of urinary excretion of DDS conjugates was the same in the dog as in man, the rates of excretion of DDS and of DDS plus DDS conjugates were greater in the dog than in man, suggesting that the acetylation of DDS to MADDS by man but not by the dog and the greater degree of plasma protein binding of DDS and MADDS by man account for the longer half-time of disappearance of DDS in man compared to that in the dog.


Comparative synergistic activity of nafcillin, oxacillin, and methicillin in combination with gentamicin against. The effectiveness of three semisynthetic, penicillinase-resistant penicillins alone and in combination with gentamicin was tested against 29 clinical isolates of enterococci. The minimal inhibitory concentrations of nafcillin were considerably lower than those of oxacillin and methicillin but were slightly higher than those of penicillin. At clinically achievable concentrations, the combination of nafcillin plus gentamicin produced enhanced killing against 13 of 14 strains of enterococci and was synergistic (by very rigid criteria) against 10 of 14 strains. In contrast, combinations of oxacillin plus gentamicin were synergistic against only 3 of 14 strains, and methicillin plus gentamicin produced synergistic killing against only 1 of 14 strains.


Antimicrobial resistance of Shigella isolated in New York City in 1973. One hundred and two Shigella sonnei and fourteen S. flexneri strains isolated from individual patients in New York City hospitals were investigated for antibiotic resistance. The S. sonnei showed 60% resistance to ampicillin and 58% to tetracycline and streptomycin. S. flexneri showed no ampicillin resistance but 50% resistance to tetracycline. There were marked differences in resistance of S. sonnei between hospitals which were not explainable by ethnic or socio-economic differences in the patient populations.


In vitro susceptibility of Pseudomanas cepacia and Pseudomonas maltophilia to trimethoprim and trimethoprim-sulfamethoxazole. Our earlier studies had shown that the two pseudomonads, Pseudomonas cepacia and Pseudomonas maltophilia, were organisms that were highly resistant to most antibiotics. The present study was undertaken to determine the susceptibility of these bacteria to trimethoprim and the trimethoprim-sulfamethoxazole combination which has been used with apparent success in treating infections caused by these pseudomonads. All 51 strains of P. cepacia were inhibited by 2 mug or less of trimethoprim per ml, whereas all 45 of the P. maltophilia were resistant to greater than 32 mug/ml. When the P. maltophilia was tested against trimethoprim-sulfamethoxazole, two strains were resistant and one only moderately resistant, but all other strains were susceptible. All P. cepacia strains were also susceptible with an average zone of inhibition significantly larger than for P. maltophilia (P < 0.005). These in vitro studies support recent case study reports of successful therapy using the trimethoprim-sulfamethoxazole combination.


Relationship between exoprotease secretion and the synthesis of ribonucleic acid and protein in Bacillus amyloliquefaciens. Studies with washed bacteria suspended in fresh medium, in which bacterial densities were altered by a factor of four so as to cause accelerated entry of exponential bacteria into the postexponential phase and to re-establish growth in postexponential bacteria, have been performed. Under all the conditions examined rifampin, at a concentration of 0.5 mug/ml, inhibited [(14)C]uracil incorporation into total ribonucleic acid (RNA) by 90 to 95%. The percentage of inhibition of incorporation of (14)C-labeled amino acids into total protein achieved in parallel experiments was less, being not more than 80%. These results suggested that non-translatable RNA synthesis was inhibited more than messenger RNA (mRNA) by the antibiotic. It was found that on slowing the growth of exponential-phase bacteria exoprotease was formed at a high rate without a lag. It was further observed that when postexponential bacteria were induced to grow, by resuspending them at a lower density, exoprotease mRNA synthesis was switched off. The only synthesis of exoprotease which occurred in this case was accountable to pre-existing mRNA during its decay. Exoenzyme formation was found to be less susceptible to rifampin than total protein synthesis.


Mechanis of chlorampenicol-cephalordine synergism on Enerobacteiaeae. A synergistic in vitro bactericidal effect of combinations of chloramphenicol and beta-lactams on strains of Enterobacteriaceae is described. The synergism is seen with strains which are resistant to the beta-lactam and is due to chloramphenicol-induced inhibition of beta-lactamase production.


Properties of the ribosomes of antibiotic producers: effects thiostrepton and micrococcin on the organisms which produce them. Ribosomes of Streptomyces azureus, which produces thiostrepton, are resistant to thiostrepton by virtue of being unable to bind the antibiotic. These ribosomes are also resistant to a number of other antibiotics (the thiostrepton group) which may share a common ribosomal binding site and a common mode of action with thiostrepton. Conversely, Bacillus pumilis and a strain of micrococcus, which produce the (probably identical) antibiotics micrococcin P and micrococcin, respectively, possess ribosomes which are susceptible to these antibiotics in vitro, although the organisms themselves are resistant.


Some effect of subinbilitory concentrations of penicillin on the structure and division of staphylococci. A strain of Staphylococcus aureus was planted on filter membranes placed on Trypticase soy agar (BBL). After incubation, the membranes with growing staphylococci were transferred to Trypticase soy agar containing a subinhibitory concentration of penicillin (one-third minimal inhibitory concentration) and again incubated. The membranes were then returned to drug-free agar and incubated once more. Counts of the colony-forming units and electron microscopy were carried out at several time intervals. When grown on agar containing penicillin, the staphylococci formed what appeared to be abnormally large cells with multiple and unusually thick septa. Examination of a number of sections showed that these large cells were in reality clusters of staphylococci that had divided but failed to separate. When these large cells were subsequently grown on drug-free agar, smaller cells and normal staphylococci emerged. Subinhibitory concentrations of penicillin do not kill staphylococci; they seem to inhibit lysis of cross walls, preventing the separation of otherwise divided cells.


Inhibition of phenylamide hydrolysis by Bacillus sphaericus with methylcarbamate and organophosphorus insecticides. The degradation of the phenylamide herbicides monolinuron, linuron, and solan by cultures of Bacillus sphaericus ATCC 12123 was inhibited by the methylcarbamate insecticides metmercapturon, aldicarb, propoxur, and carbaryl and by the organophosphorus insecticides fenthion and parathion. The extent of inhibition was largest with metmercapturon and smallest with parathion inhibition of hydrolysis of the two phenylurea herbicides was greater than of the acylanilide compound. Tests with crude enzyme preparations of aryl acylamidase derived from B. sphaericus showed that the inhibition of the hydrolysis of linuron with methylcarbamates is a competitive one. The insecticides tested did induce the enzyme, nor could they serve as its substrate.


Biodegradation of metal-nitrilotriacetate complexes by a Pseudomonas species: mechanism of reaction. A nitrilotriacetate (NTA)-degrading Pseudomonas species was shown to degrade Ca, Mn, Mg, Cu, Zn, Cd, Fe, and Na chelates of NTA at nearly equal rates when the appropriate metal concentrations are low enough to avoid toxicity from the freed metal. Ni-NTA, however, was not degraded. When higher concentrations of metal-NTA substrates were used, soil stimulated degradation of Cu, Zn, and Cd complexes, probably as a result of binding toxic freed metals. The metal associated with the NTA substrate does not appear to be transported into the cell, since metals do not accumulate in the cells and the presence of NTA reduces metal toxicity. The data are consistent with the hypothesis that an envelope-associated component, probably a transport protein involved in binding, is responsible for the disassociation of the metal from the NTA. Both soil and this NTA-degrading organism destabilize the metal-NTA complex, which suggests that in the natural environment both would act to limit mobilization of metals as soluble NTA chelates. Crude soluble enzyme preparations degrade Fe-, Mn-, and Na-NTA complexes but not Cu-NTA.


Extracellular polysaccharide from the black yeast NRRL Y-6272: improved methods for preparing a high-viscosity, pigment-free product. When the extracellular polysaccharide from the black yeast NRRL Y-6272, composed of two parts N-acetyl-D-glucosamine and one part N-acetyl-D-glucosaminuronic acid, is isolated at maximum culture viscosity, adhering black pigment gives the polysaccharide preparations a gray-to-black appearance. Precipitation of the polysaccharide from cell-free culture supernatants with either ethanol of hexadecyltrimethylammonium bromide failed to remove the pigment. Various other methods were therefore tried for obtaining a high-viscosity polysaccharide product free of pigment. By systematically varying ingredients of defined and semidefined media, an improved medium was found that not only gave polysaccharide preparations of increased viscosity, but also increased yield. A key ingredient in this medium is L-asparagine. Also, adding autoclaved bovine serum albumin or egg albumin to this medium at the time of inoculation allowed a pigment-free polysaccharide to be isolated by standard procedures. None of several other proteins of synthetic polyamides tested were as effective as bovine serum albumin or egg albumin. In an alternate approach, pink mutants obtained by irradiation of the parent black strain with ultraviolet light, apparently produce the same extracellular polysaccharide free of any pigment but in lower yields or inferior in quality.


Stability of 125I-labeled staphylococcal enterotoxins in solid-phase radioimmunoassay. Staphylococcal enterotoxins, Types A, B, and C, were labeled with 1252 by the chloramine-T method at approximately two levels of specific activity, 40 and 4 muCi/mug of protein. Toxins labeled with high specific activity showed extensive dissociation of 125I when stored at different temperatures, including -23 C. In contrast, toxins labeled with low specific activity did not show any significant loss of 125I when stored at -23 C for as long as 2 months. Enterotoxins, whether labeled with high or low activities, formed aggregates immediately upon labeling. Aggregate formation increased in high-activity-labeled toxins on storage at -23 C, and low-activity-labeled toxins showed no significant increase in aggregate formation, even after 2 months at -23 C. The aggregated forms of the enterotoxins were either devoid of antigenic activity in solid-phase radioimmunoassay or they possessed significantly reduced antigenic activity. Thus, a decrease in binding of 1252-labeled enterotoxin to specific antibody in solid-phase radioimmunoassay results mainly from (i) loss of 125I on storage, and (ii) formation of aggregates with reduced antigenic activity.


Tremorgenic mycotoxins from Aspergillus caespitosus. Two tremorgenic mycotoxins were isolated from Aspergillus caespitosus, and identified as verruculogen and fumitremorgin B. They were produced at the rate of 172 and 325 mg per kg, respectively, on autoclaved cracked field corn.


Thermal profile of a Bacillus species (ATCC 27380) extremely resistant to dry heat. Spores of Bacillus sp. ATCC 27380 were exposed at intervals to dry-heat temperatures ranging from 125 to 150 C. D-values from 139 to 2.5 h were obtained.


Fractures of the hip in the tenth decade of life. Findings in 25 cases. A report is given of the results of treatment of 25 patients with a fracture of the hip who were over 90 years of age. Twenty three patients were subjected to operation: 5 of these died in hospital, but not as a direct consequence of operation. Of the 18 patients discharged after an average hospital stay of 32 days, 13 were able to walk independently at home, on the average for over two years. It is concluded that surgical treatment of fractures of the hip in very old people is advisable and useful, provided they are in reasonable general condition and do not exhibit dementia.


Some considerations concerning the deep femoral artery. The great importance of the deep femoral artery as a collateral vessel in occlusion of the superficial femoral artery is a well-established fact. It has been found in the course of reconstructive operations of this artery that the origin of the two circumflex arteries varies considerably. A study of one hundred cadavers has given some idea of the frequency and nature of these anatomical variations. The importance of this vessel as a collateral is partially explained by the fact that the deep femoral artery has two groups of branches, both of them anastomosing with the branches of the popliteal artery. If the deep femoral artery is to function adequately as a collateral, it has to have a large caliber. An explanation for this may be found in comparative anatomy. In the phylogenetically farther advanced vertebrate animals, all of which have very strongly developed extensors in the posterior extremities, the deep femoral artery which supplies blood to this muscle group is a branch of the iliac artery, and accordingly, a pelvic artery. In man, this artery originates distal to the inguinal ligament from the common femoral artery and supplies blood to less well-developed muscle groups. In this way, phylogeny explains the large caliber of the deep femoral artery, which has originally been a pelvic artery and it also explains the numerous anatomical variations at the site of the bifurcation of the common femoral artery.


Treatment of x-ray ulcers by omental transposition. A case is reported of closure of a very deeply penetrating X-ray ulcer of the axilla. Omental tissue was used as a pedicle flap and the advantages of this procedure to cover and salvage ischaemic tissue are pointed out.


Penile cancer.

Penile cancer. A retrospective study was made of the case histories of 91 patients with a penile tumor. The tumor histology of 56 patients could be re-evaluated, confirming the diagnosis: epidermoid cancer. Fifty three of these 56 patients were treated more than five years before the retrospective evaluation. Penile carcinoma has not increased in frequency during the last few decades. No correlation could be found between venereal diseases and penile carcinoma, nor between the duration of symptoms before treatment and the development of metastases. Amputation is the treatment of choice. Lymph node dissection must be performed when metastatic disease is suspected. When patients die of tumor, this is caused by metastatic disease, but in about 50 percent of cases the patients can be saved by dissection of positive nodes, preventing a further extension. More than 70 percent of 53 patients have survived for at least five years without evidence of recurrence or metastatic disease including six (out of 11) patients in whom the dissected inguinal lymph nodes showed involvement. In this series of patients cytostatic therapy was not used. Bleomycin is known to have a definite action on these tumors, but only the far future can show if better results are to be expected with a combination of the described therapy with cytostatic drugs.


Rhabdomyosarcoma of the esophagus.

Rhabdomyosarcoma of the esophagus. Case report of a woman aged 63 years suffering from a rare lesion: rhabdomyosarcoma of the esophagus. Surgical treatment was successful: over a year postoperatively the patient was in good condition. A review is presented of the ten cases reported in world literature. Etiology, morbid anatomy and treatment are discussed.


Sweat gland carcinoma with regional lymph node metastasis. Description of a 63-year-old man with a sweat gland carcinoma low in the left axilla, and an axillary lymph node metastasis. A five-year survival was obtained. The histological picture of a sweat gland carcinoma may be highly variable. The best treatment seems to be local excision. If the primary tumour is situated close to a regional lymph gland station, regional lymph node extirpation should be seriously considered.


Ultrastructural studies in epidermolysis bullosa heriditaria. I. Dominant dystrophic type of Pasini. Ultrastructural examination was performed in 8 biopsies from 4 patients with the Pasini type of epidermolysis bullosa dystrophica dominans. The biopsies were taken from: 1. clinically normal skin from nonpredilection areas, 2. intact skin from predilection areas, 3. involved skin and 4. experimentally frictioned skin. The main ultrastructural alterations detected are as follows: hypoplasia of anchoring fibrils, split or blister formation between basal lamina and dermis, hernia-like protrusion of basal cells, sub- and intraepidermal deposition of fibrillar bodies, and duplications of basal lamina. Among them, the constantly observed finding in all of the four biopsy groups in the structural defect of anchoring fibrils, namely, that the anchoring fibrils are rudimentary and reduced in number. Presence of the structural defect of anchoring fibrils in clinically normal skin from nonpredilection areas in patients with the Pasini type of epidermolysis bullosa dystrophica dominans indicates that this defect is not a secondary change following repeated mechanical trauma, but a primary, genetically determined event.


Mycosis fungoides with marked brain involvement--a case report. The clinical course of a patient with mycosis fungoides, which could be confirmed histologically in the premycotic stage, 2 years after the onset of the disease is reported. The disease led to death after a further 3 years, during which the infiltrative and tumorous stage had appeared. At autopsy, apart from the skin changes typical for mycosis fungoides, involvement of the pia mater, plexus chorioideus, cerebrum and cerebellum was established. This constituted the only manifestation of the disease in the internal organ systems. There were no detectable neurological defects.


Immunity in tumours of the skin. Studies on cell-mediated immune reactions. Cell-mediated immunity (CMI) was investigated in a series of patients with epithelial tumours of the skin and with Kaposi's sarcoma. In all 53 patients the peripheral blood lymphocyte count showed no substantial difference from the control values. The blasts count after phytohaemagglutinin stimulation in 30 patients ranged from 40-50% with no noticeable difference from the control values. Intradermal tests with the staphylococcal antigen, PPD-tuberculin and streptokinase-streptodornase carried out in 59 patients proved negative in a significant number of cases, mainly those of Kaposi's sarcoma. The non immune inflammatory response to chemical irritant (benzalkonium chloride) was more often negative (17 of 59 cases) than in controls (5 of 30 subjects). The DNCB sensitization test carried out in 28 patients was negative in 5 cases (2 cases of late basal-cell epithelioma, 2 cases of advanced squamous-cell carcinoma and 1 case of Kaposi's sarcoma). The findings do not thus indicate the presence of a gross CMI defect in the material studied, which would be borne out by all the tests employed. The sometimes discordant results of the various tests suggest the existence of partial CMI defects in certain tumours, but mainly in Kaposi's sarcoma. Such partial defects, encountered even in early neoplasms, coexist, in some cases, with failure of inflammatory response to chemical irritants.


The effect of systox on rubidium absorption by excised barley leaf tissue. The influence of various concentrations of the thiol isomer of Systox on Rb absorption by excised barley leaf tissue was compared with the effect of DNP and DCMU. Rb absorption, regardless of the external salt concentration, was progressively reduced as the Systox concentration in the external solution was increased from 0.25 to 1.0 mM. Under anaerobic conditions, light-enhanced Rb absorption by leaf tissue was not influenced by Systox treatments. DNP treatment reduced ion absorption by leaf tissue. In the dark, the relative inhibitory effect of DNP and Systox treatment on Rb absorption was greater than in the light. The combination of Systox plus DNP inhibited Rb absorption more than did separate treatment with either compound. DCMU treatments in the light resulted in a reduction of light-enhanced Rb uptake. Also in the light, the combination of DCMU with Sytox, DNP, or both, inhibited Rb uptake more than did separate treatments of Systox, DNP, or Systox plus DNP. It is suggested that the inhibitory effect of Systox on Rb absorption by leaf tissue is due to partial inhibition of oxidative phosphorylation. Moreover, since light-enhanced Rb absorption is not affected by Systox, it is concluded that Systox has no effect either on the photophosphorylation reactions or on the utilization of high-energy phosphorylated compounds.


Distribution of HEOD (dieldrin) in mammals: II. some applications of the preliminary model. The preliminary model of the lipid-phase pharmacokinetics of dieldrin in mammals is applied to evaluation of the probable role of auto-induction, the effect(s) of growth, and the role of compartmentalization. Realistic simulations and comparison to actual data permit the conclusion to be drawn that induction of its own metabolism plays a relatively monor role in the distribution and level of dieldrin residues. Although some of the effects of growth are resonably well simulated, the model as constructed does not permit compartmentalization. It was concluded that the model should be revised to include aspects of the as-yet quantitatively unknown intracellular binding and membrane transport within the flow-limited model.


Residue of organochlorine compounds and mercury in birds' eggs from the Niagara Peninsula, Ontario. Eggs (307) were collected in 1971 from twenty species of birds with a variety of feeding habits from the Niagara Peninsula. This area of ontario is intensively developed for agriculture and heavy industry and has a large urban population. Representative species were obtained from both the terrestrial and aquatic food chains. Eggs were analyzed for organochlorine insecticides, polychlorinated biphenyls, and total mercury. Eggs from carnivorous species at the top of the aquatic food chain had the highest mean residues of signa DDT(7.6to 22.4 pm), PCB (3.5 to 74.0 ppm) and total mercury (0.64 to 0.83 ppm). Eggs from some terrestrial carnivores (red-tailed hawk and great horned owl) also had relatively high residues (2.5 to 3.9 ppm of sigmaDDT, 0.2 to 1.0 ppm of PCB, 0.06 to 0.09 ppm of mercury, however levels were much lower than those found in eggs from aquatic-feeding carnivores. Eggs from one red-shouldered hawk had residues comparable to the aquatic feeding carnivores. Eggs from herbivorous and insectivorous birds of both aquatic and terrestrial environments contained much lower residues. PCB residues were slightly lower in eggs among the terrestrial feeding species (0.05 to 2.0 ppm) than among the aquatic feeders (0.14 to4.0 ppm) and tended to be lower in eggs from terrestrial species collected in rural than incity environs. Levels of sigmaDDT were similar in both groups with eggs from terrestrial feeders containing mean resisues between 0.15 and 2.64 ppm and those from aquatic feeders between 0.33 and 2.79 ppm.


Volatility of fungicidal mercury compounds on wheat seeds. The volatility of two fungicidal seed dressings, Panogen 15 B liquid and Panogen PX powder, containing methyl mercuric dicyandiamide in equivalent amounts at the dosage used, was compared with that of triple distilled mercury. Tests were made in the absence and presence of cleaned Manitou wheat of 12.0% and 17.1% moisture content. The Panogen formulations were compared at the recommended and twice the recommended rate at different dosages, storage periods and storage temperatures. The Hg content of air samples was determined by the Corte-Monkman method, capable of determining 0.4 ng of Hg, which in a 1-L air sample is equivalent to 0.049 ppb (v/v). The volatility of the interstitial air expressed as mug of Hg vapor/m3 air depended on temperature, wheat moisture content and storage duration and ranged from 150 to 2,240 for metallic Hg, 21 to 350 for Panogen 15 B, and 31 to 380 for PX. In the absence of wheat the volatility of 15 B was greatest (395) at -17.5 degees C and least (75) at 4.5 degrees C, but increased rapidly thereafter with increased temperature. Volatility of metallic Hg after application to wheat of 12.0% and 17.1% moisture content was not significantly reduced after four days storage, but that of Panogen 15 B and PX was reduced considerably, particularly at the higher moisture level. Thus, volatility of mercurial seed dressings cannot be predicted from Hg content alone. Reduction of volatility through possible irreversible chemical bonding of Hg with seed components is suggested for more detailed investigation.


Mercury vapor as an atmospheric contaminant of dental offices. Airborne mercury from dental offices was selectively trapped by silber gauze elements in borosilicate glass obsorbers, followed by heat-desorption and spectrophotometric measurement at 2537A. As little as 0.4 ng of Hg could be accurately determined, which is equivalent to 49 ppt in a wone-L air sample on a v/v basis. Over 860 air samples were taken over a range of locations and working conditions at 88 different dental offices, and at the Dental Training Clinic of the University of Manitoba. The Hg vapor concentrations at the dental facilities ranged from 0.45 to 742 mug/m3 of air, 29% of the samples were within 0.45 to 5 mug; 37.8 were within 5.1 to 25mug;and 33.2% were above 25 mug. Mercury concentrations varied during the working day, depending on the time of sampling, the number of amalgams placed, and the interval between placements. The lowest concentrations were obtained in the morning. Disturbance of residual mercury droplets on floors or working areas by sweeping or dusting, or immediately after attempted clean-up of a mercury spill, sharply increased the amount of airborne mercury.


Plasticizers in the environment: the fate of di-N-octyl phthalate (DOP) in two model ecosystems and uptake and metabolism of DOP by aquatic organisms. The fate of the plasticizer, di-n-octyl phthalate (DOP) has been examined in 33-day terrestrial-aquatic and three-day aquatic model ecosystems. The five organisms of the two systems contained residues of DOP, demonstrating the propensity of this lipoid soluble organic molecule to be concentrated from the water. The residues in the organisms in the three-day system were higher than in the 33-day system with the exception of the fish, indicating perhaps, that DOP can undergo some degradation before the fish is placed in the system on the 30th day. A half-life of five days for DOP disappearance from the water was calculated from water samples taken periodically. Further, effects of mixed function oxidase and esterase inhibitors were investigated on the metabolism of DOP by various selected organisms and tissues of the two ecosystems.


The effect of Systox on ionic fluxes in excised barley roots. The influence of various concentrations of the thiol isomer of Systox on ionic fluxes in excised barley roots was investigated. For purposes of comparison, treatments with DNP alone, or in combination with the Systox isomer, were included. Rb and Cl absorption, regardless of the external salt concentrations, were progressively reduced as the Systox concentration in the external solution increased. Treatment with Systox did not result in any appreciable increase in the efflux rates of Rb or Cl ions. DNP treatment enhanced the efflux of Rb but not of Cl. The increased efflux was too small to account for the reduced net uptake. A comparison of individual and combined effects of Systox and DNP on ion absorption indicated an independent action of the two inhibitors.


Experimental studies on human health effects of air pollutants. II. Four-hour exposure to ozone alone and in combination with other pollutant gases. Eight adult male volunteers were exposed to ozone (O3) alone and then in combination with nitrogen dioxide and carbon monoxide under conditions simulating ambient air pollution exposures. Four "normal" men showed few or no effects from repeated exposures. Four male volunteers with a history of "hyperreactive" airways, but with normal base line pulmonary function spirometric studies, after O3 exposure developed definite symptoms and decrement in pulmonary function.


Experimental studies on human health effects of air pollutants. III. Two-hour exposure to ozone alone and in combination with other pollutant gases. Adult male volunteers were exposed to ozone (O3) at 0.25, 0.37, or 0.50 ppm, and to O3 in combination with nitrogen dioxide (NO2) and carbon monoxide (CO), with secondary stresses of heat, intermittent light exercise, and repeated exposure. Few important physiological changes, and only mild symptoms, were found with 0.25 ppm O3, with 0.25 ppm 03 plus 0.30 ppm NO2, or when 30 ppm CO was added to the latter mixture. With 0.37 ppm O3, more symptoms were present and some subjects developed definite decreases in pulmonary function. With 0.50 ppm O3, most subjects had symptoms and about half showed substantial pulmonary function decrement. In reactive subjects exposed on two successive days, changes were usually greater the second day, indicating that effects of successive exposures were cumulative.


A perspective on environmental health in the USSR: research and practice. Under the auspices of the US-USSR agreement for cooperative research in environmental health, Soviet methods for setting and enforcing standards for environmental pollutants were observed. Since all industry is government owned, the Soviet government is the principal polluter of the environment, the regulator of environmental degradation, and supporter of research on environmental quality control. The Sanitary Epidemiological Service, a subdivision of the Ministry of Health, coordinates the activities of many of the research institutes involved in environmental research as well as a large network of Sanepid Stations for maintaining and controlling environmental quality at the local level. The Soviet Union's distinctive view of a pollutant standard has greatly influenced the environmental research that is undertaken. The centralized absolute power of the government to enforce pollution abatement has led to some improvements in environmental quality.


Reproductive ability of workmen occupationally exposed to lead. The reproductive ability of 150 men occupationally exposed to lead were studied by clinical and toxicological analysis. Subjects were divided into four groups: lead-poisoned workmen (23) and those showing a moderate (42), slight (35), or physiologic absorption (50). Findings show that (1) Lead poisoning as well as moderate increased absorption of lead decrease the fertile ability of men. An increased frequency of asthenospermia, hypospermia, and teratospermia have objectified the decrease. (2) Slight increased or physiologic absorption of lead do not significantly influence the fertile ability of workmen. (3) Hypofertility induced by lead is due, perhaps, to its direct toxic effect on the gonads, as no interference with the hypothalamopituitary axis were evidenced.


Time and causation in studies of long-term exposure to environmental factors. The various shortcomings of the prevalence study as an instrument for causal research are evaluated by comparing the prevalence design with the classical experimental design. On the basis of these shortcomings it is suggested that epidemiologists refine their research strategies in two respects, both related to time. (1) it is suggested that they include formerly exposed as well as presently exposed in their sampling frames and (2) that they avoid using present status with respect to causal factors as indicators of life-experience of these factors in analysis. On the basis of some studies of the relationship between long-term exposure to presumed noxae and chronic lung disease, numerical examples of the undesirable consequences of ignoring time are given.


DNA polymerase activity in rheumatoid synovial membranes. RNAase-sensitive DNA polymerase activity was demonstrated in synovial membrane preparations from 23 out of 25 rheumatoid arthritis patients. Control groups consisted of twelve patients with osteoarthrosis, four with secondary osteoarthrosis, and twelve with other conditions. The last group showed no activity, while the results with the other two groups were varied. The properties of the polymerase enzyme, such as its stimulation by synthetic templates and inhibition by actinomycin D, were not consistent with it being associated with an oncogenic virus; it seems to be more like that found in stimulated normal human lymphocytes, described as an RNA-primed DNA-directed DNA polymerase.


Proliferation of synovial lining cells and fibroblasts. After in vitro incubation with 3H-thymidine, the proliferation of synovial lining cells and fibroblasts was investigated in surgically-removed articular tissue. Under normal conditions, in nonrheumatoid arthritis and in osteoarthrosis, low proliferation rates for both cell types were observed. In rheumatoid arthritis, the rate of proliferation of both cell types was usually increased. An increased proliferation of the synovial lining cells was especially observed in cases with a hyperplastic lining cell layer and in cases with a minimal lymphocytic and plasma cellular infiltration in the synovial membrane.


Relationships between rheumatoid cells in culture. Rheumatoid synovial fluid macrophages are compatible with synovial membrane fibroblasts in mixed cell culture. They do not appear to have had any immunological experience recognized by homologous rheumatoid blood lymphocytes. The fusion between macrophages which often takes place in cultures of rheumatoid synovial fluid cells seems to be the result of a cell membrane change between contiguous cells rather than to the release of of a 'fusion factor'. Other combinations and manipulations of the rheumatoid cell population may yet prove fruitful in the search for cell-associated phenomena important in the pathogenesis of rheumatoid disease.


Double-stranded RNA antibodies in systemic lupus erythematosus. Antibodies to viral double-stranded RNA (ds RNA) have been found in 40% of patients with systemic lupus erythematosus (SLE) and 14-5% of patients with rheumatoid arthritis. These antibodies were diagnostically more specific SLE than those directed against artificial polynucleotides, poly I:C and poly A:U. Although not disease specific, high titres of antibody to ds viral RNA were found almost exclusively in SLE. Serial studies failed to show that RNA antibody levels correlated with disease activity. Although of considerable interest in experimental studies on the pathogenesis of SLE, ds viral RNA antibodies are of little clinical significance in the management of SLE.


Raised serum creatine phosphokinase activity in ankylosing spondylitis. Serum enzyme studies were made on 43 (37 male, 6 female) consecutive patients with ankylosing spondylitis. Serum creatine phosphokinase (CPK) activity was raised above 55 IU/l in 24 (65%) of 37 male patients (range 29-165 IU/l, mean 68) as compared with 2 (4%) out of 47 male controls (range 14-85 IU/l, mean 33: P less than 0-001); levels were greater than 35 IU/l in six (100%) out of six female patients (range 39-100 IU/l, mean 56) as against one (3%) of 35 female controls (range 3-106 IU/l, mean 16; P less than 0-001). The recognized pitfalls in interpreting CPK activity were avoided. In all of sixteen randomly selected patients isoenzyme studies confirmed that muscle is the source of the enzyme. There was a significant correlation between CPK activity and both spinal flexion and the reciprocal of finger-to-floor distance (P less than 0-5 in each case).


Clinical and biochemical observations on three cases of hypoxanthine-guanine phosphoribosyltransferase deficiency. Clinical and enzymatic studies on two brothers with severe deficiencies of erythrocyte hypoxanthineguanine phosphoribosyltransferase (HGPRTase) are described, and are compared with similar studies of a classical case of the Lesch-Nyhan syndrome from another family. The two brothers have no neurological abnormalities, only traces of erythrocyte HGPRTase, erythrocyte adenine phosphoribosyltransferase activities approaching the high levels found in the Lesch-Nyhan patient, and similarly raised plasma and urinary concentrations of uric acid. Despite these strong biochemical similarities between the three patients, there were wide differences in the clinical case histories. In both families the enzyme deficiency appeared to be inherited as an X-linked character through asymptomatic carrier females. The relationship of HGPRTase deficiencies to the Lesch-Nyhan syndrome is discussed. Some observations relating to techniques are reported. Cellulose acetate has been found to give much better separations of labelled reaction products in low-level phosphoribosyltransferase assays than filter paper, when used as a supporting medium for electrophoresis. The analysis of hair follicles gives indications of individuals heterozygous for the enzyme deficiency, but the proportion of enzyme-deficient follicles was very small, and the test needs support from studies of other cell types. Using haemolysates, there were signs of a slow indirect conversion of hypoxanthine to inosinic acid, via inosine. Inosine appears to be labelled by a ribosyl-transfer reaction.


Pigmented villonodular synovitis in multiple joints. Occurrence in a child with cavernous haemangioma of lip and pulmonary stenosis. A case is presented of pigmented villonodular synovitis involving three joints in a 7-year-old girl. The diagnosis was confirmed at surgery and by histology. The patient also exhibited a haemangioma of the upper lip and a congenital pulmonary stenosis of mild degree. Subtotal synovectomy of the right knee and of both ankles was performed. The lesion recurred in both ankles after 6 months. Review of the literature failed to reveal any previous report of multiple joint involvement by pigmented villonodular synovitis in childhood and it appears that simultaneous involvement of three joints has not previously been described. Scintiscanning with 99mTc stannous pyrophosphate showed increased vascularity of the involved joints immediately after injection, but no increased osteoblastic activity was seen on the delayed scan. This radionuclide scanning technique is therefore helpful in distinguishing pigmented villonodular synovitis from other arthropathies.


Pharmacokinetic rationale for a malarial suppressant administered once monthly. Serum was collected from six adults participating in a field trial of sulfadoxine and pyrimethamine in combination which was being administered once monthly for malaria suppression. Samples were drawn during each of two consecutive months three hours, and 7, 14 and 28 days following a dose of 1 500 mg sulfadoxine. Serum sulfadoxine concentration was measured using the method of Bratton and Marshall (1939). Initial serum concentrations averaged 19-9 plus or minus 2-4 (SD) mg/100 ml and decayed to 6-2 plus or minus 2-8 mg/100 ml at 14 days. Serum sulfadoxine concentrations were still detectable at 28 days following a dose (2-1 plus or minus 1-5 mg/100 ml). Elimination half-time averaged 195 plus or minus 44 hours. The presistent serum concentrations of sulfadoxine following monthly doses documented here during field-use of this drug are in agreement with the successful clinical results reported for such a regimen (Lewis and Ponnampalam, 1974; O'Holohan and Hugoe-Mathews, 1971; Wolfensberger, 1971).


New observations on the malaria parasites of rodents of the Central African Republic - Plasmodium vinckei petteri subsp. nov. and Plasmodium chabaudi Landau, 1965. The morphology and enzyme forms of malaria parasites isolated from 50 wild caught specimens of Thamnomys rutilans from the Central African Republic have been studied and three distinct species of Plasmodium identified. One species has been confirmed as Plasmodium yoelii yoelii. Morphological features of both the remaining species correspond to those given by Landau (1965) in her original description of Plasmodium chabaudi. For one of these species the name P. chabaudi has been retained; the other species, which closely resembles subspecies of Plasmodium vinckei from other regions of Africa, has been designated Plasmodium vinckei petteri subsp. nov. P. chabaudi and P.v. petteri are distinguished from each other both in their morphology in the blood and sporogonic stages, and in their enzyme forms.


The pathology of naturally-occurring bovine schistosomiasis in the Sudan. The gross and histopathological lesions of naturally-occurring bovine schistosomiasis in the Sudan are detailed. Out of 61 animals examined, 53 were found infected with Schistosoma bovis, showing lesions in their livers, intestinal tracts and other organs. Apart from granulomas, periportal inflammatory infiltration, fibrosis and pigmentation of Kupffer cells, livers of infected cattle revealed peculiar lesions in the form of "nodular sclerosis", medial hypertrophy of portal veins and lymphoid nodule and follicle formation around parasites. In the intestines, variable manifestations of catarrh, with eosinophilic infiltration, granulomatous reaction and vascular changes, were observed. Pancreatic schistosomiasis was common and some animals had lesions in their lungs and lymph nodes. Urogenital lesions, rectal and colonic polyps, congestive splenomegaly, gastro-oesophageal variaces and Symmer's clay-pipe stem fibrosis of the liver were not seen in cattle. The haematological and serum protein findings in infected animals were included. The findings were related to the lesions observed and the need for detailed study of functional disturbances in bovine schistosomiasis is indicated.


Mekong schistosomiasis. III: a parasitological survey of domestic water buffalo (Bubalus bubalis) on Khong Island, Laos. Of 103 water buffalo (Bubalus bubalis) examined on Khong Island by means of the M.I.F.C. and hatching techniques, none were passing eggs resimbling those of the Mekong schistosome. One buffalo calf was infected with Orientobilharzia harinasutai and another with Schistosoma spindale; this is the first time these parasites have been reported from Laos. Since the buffalo that were examined had constant and year-round access to a part of the Mekong River that has been shown to be a site of heavy transmission of schistosomiasis to humans and dogs, it was considered that the buffalo would have acquired the infection with the human Mekong schistosome if this were possible. In the absence of buffalo necropsies, and since no eggs of the Mekong schistosome were detected in the stools of these animals, we assumed that they had either not become infected with this parasite or, if they had, that the infections did not produce eggs in the faeces which were detectable by the methods employed. On the basis of our examinations, it would not seem that domestic water buffalo are involved as reservoirs in the epidemiology of human schistosomiasis on Khong Island.


A comparative study of the relative efficacy of pyrantel pamoate, bephenium hydroxynaphthoate and tetrachlorethylene in the treatment of Necator americanus infection in Ceylon. The clearance of hookworm (Necator americanus) ova by a single dose of tetrachlorethylene (T.C.E.) was compared with that produced by single and multiple dose regimes of bephenium hydroxynaphthoate and pyrantel pamoate. Single doses of bephenium and pyrantel were inferior to T.C.E. Three daily doses of bephenium or pyrantel produced effects comparable with a single dose of T.C.E. Because of the low cost and lack of side effects, T.C.E. remains the drug of choice in the treatment of N. americanus in infections; the only disadvantage of T.C.E. is its unnoticed deterioration under tropical conditions.


The influence of stream geology on the distribution of the bilharzia host snails, Biomphalaria pfeifferi and Bulinus (physopsis) sp. The Gladdespruit and Komati River surveys have shown that similar environmental conditions have developed where the watercourses flowed over particular rock types. In these watercourses a potentially useful association was found between the occurrence of permanent, lentic habitats produced by the weathering of bedrock with a hardness above 5 in Mohs' Scale of Hardness and the longitudinal distribution of persistent populations of the bilharzia intermediate host snails Biomphalaria pfeifferi and Bulinus (Physopsis) sp. Bilharzia transmission follows this pattern in these waterways. Weathering of bedrock with hardness below 5 in Mohs' scale, and/or flow over beds of alluvial sand, produced perpetually lotic (flowing) environments without persistent host snail populations because of the snail's inability to tolerate high current speeds. However a few temporary populations survived in temporarily lentic habitats during the dry winter season.


Aerial application of N-trityl morpholine to irrigation canals in Sudan. Using a crop-spraying aircraft modified to give a coarse spray, the feasibility of aerial application of the molluscicide N-trityl morpholine to minor canals on the Gezira has been proved. In January 1973, seven canals were sprayed at dosages of 0-1 p.p.m., 0-2 p.p.m., 0-5 p.p.m. and 1-0 p.p.m. Chemical analysis indicated that about 70% of the chemical was present in the water 5-15 hours after the spray, and snail exposure to the sprayed canals indicated that all dosages applied were lethal to Biomphalaria snails. Bulinus snails, which are less susceptible to the molluscicide, were killed only by the 0-5 p.p.m. and 1-0 p.p.m. dosages. Sampling of the natural snail populations of the canals confirmed these results. In March 1973, an area of 464 sq km was treated by drip-feed of 0-1 p.p.m. N-trityl morpholine to kill snails in the main and major canals, and then by aerial spraying 56 of the 58 minor canals in the area. Despite the high winds which disrupted the spray timetable, the canals were successfully treated in 9-5 hours flying-time within seven days. A very high initial snail kill was indicated by both caged snail exposure and natural snail population sampling. However, in excellent snail breeding conditions the area was reinfested with snails within two months. The cost of the application was only 5% of the chemical cost, and aerial spraying in March and May will almost certainly be incorporated in an annual snail control programme.


New observations on the epidemiology and pathogenesis of sporotrichosis. Five uncommon cases of skin sporotrichosis are presented, including a small family outbreak with interesting epidemiological findings and two patients treated with corticosteroids; we attributed the severity of the lesions to the steroids. Mice were used to confirm our hypothesis on the pathogenesis. The pathological findings in case of sporotrichosis in a dog are presented. A group of 359 pulmonary patients was tested with two different antigens of Sporotrichum schenkii.


Isoenzymes of two aminotransferases among Trypanosoma vivax in Nigerian cattle. During a period of three months, thin-layer starch-gel electrophoresis was used to examine the isoenzymes of alanine and asparate aminotransferases from samples of T. vivax collected from naturally infected Nigerian cattle. Experimentally infected cattle sheep and goats were also studied. Three patterns, termed Sets 1,2 and 3, differed in both enzymes. The stability of the enzyme patterns was generally confirmed in experimental animals. The results are discussed in relation to subspeciation in T. vivax.


Electrophoretic investigation of some dehydrogenases in Leishmania amastigotes. Amastigotes of Leishmania mexicana mexicana and of Leishmania donovani were grown in mouse peritoneal macrophages and dog sarcoma cells in culture. Polyacrylamide gel disc electrophoresis of amastigote-infected tissue cultures failed to detect parasite lactate dehydrogenase and malate dehydrogenase, although the presence of glucose-6-phosphate dehydrogenase was indicated.


The experimental chemotherapy of leishmaniasis. II. The activity in tissue culture of some antiparasitic and antimicrobial compounds in clinical use. A variety of compounds used in the treatment of parasitic or bacterial infections in man, including leishmaniasis itself, were examined for their activity against three lines of Leishmania in tissue culture. The organisms used were L. mexicana mexicana, L. tropical major and L. donovani; they were grown in dog sarcoma and hamster peritoneal exudate cell lines. Leishmanicidal activity was observed in a number of compounds currently in clinical use for the treatment of one or other form of leishmaniasis. Cycloguanil, nifurtimox, amphotericin B and monomycin were effective but pentamidine showed poor activity. In each case marked differences were observed in the level of response in the different parasite lines. Organic antimonials were most active when anmastigotes were exposed to them prior to entry of the parasites into host cells. This suggests that such compounds may exert an effect on amastigotes during their brief extracellular transit from one host cell to another in vivo. A number of antimalarials showed good to moderate leishmanicidal action, particularly against L. mexicana and L.t. major. Several schistosomicidal agents also possessed leishmanicidal properties. The commonly used broad spectrum antibiotics showed little if any activity. In discusssion a comparison is drawn between data published on the action of some of these drugs against L.t. major in mice and our observations with the same strain and L. mexicana in tissue culture. A remarkably good agreement is found for most of the compounds examined. General agreement is also noted between these data and reports of clinical trials although it is not possible to draw too many conclusions because of the failure in most clinical studies to make an accurate identification of the causative Leishmania. It is concluded that, although the tissue culture model is not to be considered as ideal and can probably be improved, data obtained by its use do bear relevance to the action compounds in vivo, and the model may be use in the screening of drugs for leishmanicidal activity.


Storage and sexual separation of Glossina morsitans morsitans Westwood puparia. Maintenance of unknown-age tsetse puparia at 4 degrees C for six days substantially reduced emergence; normal emergence occurred when puparia were held at temperatures of 12 degrees, 14 degrees, or 16 degrees C for two, three or four weeks, respectively. In-storage eclosion of adults was either suppressed completely at the temperatures used or was slight. Weight, puparial duration, and density of puparia were examined in an attempt to detect sexual differences in puparia. There appeared to be no usable correlation between pupal weight and sex, but the difference between the puparial duration of each sex offers a mechanism for retaining 81% of the females produced and releasing 84% of the males. The flotation of unknown-or known-age puparia in methanol-water solutions of varying specific gravities demonstrated some diffences in the density of male and female puparia. However, these differences were not great or consistent enough to provide an efficient system of separating puparia by age or sex.


A preliminary survey of the prevalence of Mansonella ozzardi in some rural communities on the river Purus, state of Amazonas, Brazil. Three hundred and eighty-six blood films were taken from mesticos (persons of mixed race) in villages on the river Purus, Amazonas; 17(4-4%) were infected with Mansonella ozzardi. An average of 11-2 microfilariae/20 mm3 of blood (range 1-103) were found in infected persons. No statistical difference was found between the infection rates of males and females. Seringueiros (rubber collectors) and lavradores (agricultural workers) showed similar high infection rates, compared to people with indoor occupations. Rubber-collecting communities showed a higher infection rate with M. ozzardi than villages economically dependent on the local municipal town. It is suggested that this was due to greater numbers of infective vectors in these locations, and to the higher proportion of the human population working outdoors.


[Pseudocoarctation of the aorta. Association with cardiopathy or vasculopathy]. Two cases of aortic pseudocoarctation were presented, the first one associated to rheumatic heart disease and the other one with an added obstruction of the left subclavian artery due to an angulation. The alterations of the subclavian arteries due to obstruction have been described very few occasions because they are usually asymptomatic. In our case there was only tiredness of the affected limb. The association of pseudocoarctation with rheumatic heart disease has been never reported, but we consider it to be just a mere coincidence. After reviewing what has been reported, we conclude that since the aortic pseudocoarctation is a benign sickness, the only thing to be done is to check these patients periodically.


Central anticholinergic actions of doxepin in rabbits. Neuropharmacological effects of doxepin were studied in rabbits to reveal fundamental actions which might explain its clinical efficacy. The results indicate that central effects of this compound are similar to those reported for atropine and the tricyclic antidepressants. In this regard, doxepin produced mydriasis and EEG synchrony without producing overt signs of sleep. It inhibited in a dose-related manner the EEG activation produced by physostigmine. It inhibited the EEG, but not behavioral, effects of methamphetamine. Doxepin enhanced some of the behavioral effects of methamphetamine, as does atropine.


Human intramyocardial oxygen detected through chronic polarographic electrodes. The intramyocardial PO2 was studied in 7 patients after cardiac surgery, by means of a long-term electrode implanted subepicardically in the free wall of the left or the right ventricle, utilizing the polarographic method. Inhalation of 100% O2 or 5% CO2 +95% O2 provoked maximal increases in the myocardial PO2. In most cases intense exercise, and the Valsalva manoeuvre caused a decrease in the PO2. Intravenous propranolol slightly increased the PO2 in one case. Other drugs used in coronary patients caused inconstant effects. Sleeping decreased the heart PO2 in one case. This technique appears to be a useful tool for studying the human intramyocardial PO2 during a period of several weeks.


Long-term effect of amphotericin B on serum cholesterol in the rat. Amphotericin B (1mg/kg/day) was administered intravenously to rats for 30 days, with simultaneous sham (5% dextrose in saline) injections to control animals. After four treatments, serum cholesterol concentration among treated animals demonstrated a maximum decrease of 25% (p less than 0.005) from the control level. Serum cholesterol returned to control level after three more treatments, and no significant difference (p greater than 0.05) was observed in experimental animals, despite continued treatment thereafter. Various hematological and biochemical parameters were monitored at intervals during this period. Except for significantly elevated (p less than 0.001) plasma urea nitrogen in treated animals, no significant difference was observed between the control and treated animals with regard to other parameters. Gross examination at autopsy, followed by microscopic study, showed absence of organ pathology.


[Gap phenomenon in the bundle of his conduction]. His bundle electrograms recorded during atrial stimulation with the extrastimulus technique permitted the analysis of the so called gaps in bundle branch conduction. Three different types of gaps were identified each with a distinct electrophysiological mechanism. In type I gap a CLBBB pattern disappeared at shorter coupling (A1-A2) intervals because the more premature impulses encountered a greater degree of the delay at the A-V node therefore reaching the left bundle branch after its effective refractory period had ended. During this part of the cycle the H1-H2 were longer and H2-V2 intervals shorter than when CRBBB was present. In type II gap a CRBBB pattern disappeared at shorter coupling intervals because the premature impulses met a greater delay in the proximal portions of the His-Purkinje system. In consequence, they arrived at the right bundle branch when its effective refractory period had expired. When this occurred the H1-H2 interval were shorter and the H2-V2 longer than those at which CRBBB had been present. The patient with type III gap had CLBBB. A-V conduction was possible through the right bundle branch very late in the cycle. However, it could not occur at shorter coupling intervals finally reappearing at even shorter coupling intervals. True supernormal conduction or vagal pulsatile discharges could have been present. Yet, we favor, as the most likely possibility, the existence of 2:1 phase 4 block with latent or abortive escapes not recorded in the surface leads.


Congenital heart disease in patients with anomalous intrathoracic heart location. The purpose of this paper is to analyze 107 patients with anomalous heart location, divided into 6 main group, depending on type of heart formation, location of cardiac apex and topography of abdominal viscera. In most of the patients the associated congenital cardiac defects that were diagnosed were extremely severe, multiple, and cyanotic. Biplane angiocardiography is the most valuable instrument in the diagnosis of anomalous heart location. Surgical treatment of congenital cardiac defects in the presence of anomalous heart  location has specific features, but in most of the patients these anomalies did not interfer with the total correction of potentially correctable defects.


Ontogenesis of monoamine oxidase and catechol-O-methyl transferase in various tissues of domestic swine. Activities of monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT) in liver, kidney, heart, spleen, hindbrain, and adrenal glands were compared in adult dogs, cats, guinea-pigs, rabbits, rats, sheep, and 150-day-old swine. Swine had the highest COMT activity and dogs or cats, the lowest in most tissues. MAO was more tissue and species variable. The ontogenesis of MAO or COMT was evaluated in the same six tissues of swine from 10 days before birth through 150 days of age. COMT and MAO generally increased in swine kidney and liver with age, but the developmental patterns were more variable in other tissues. COMT increased in heart, spleen, and adrenals through 14 days of age, decreased in spleen and adrenals to 150 days, but remained elevated in heart. Brain MAO activities were near or above 150-day-old levels at birth and changed little with age. Cardiac MAO fell from birth to 70 days of age, while splenic and adrenal activities increased with age. MAO substrate specificity to tyramine, benzylamine, and serotinin along with selective inhibition by harmine, pargyline, and clorgyline were used as indices of multiple enzymic forms. Type B MAO may dominate in all swine tussues except spleen, although the biochemical characteristics of this enzyme form do not seem to fit all of the patterns described for other species. Thermal stability of MAO in swine resembles that in the guinea-pig.


[Disulfiram and digestive motility; effect on absorption of ethanol in the rat]. The influence of disulfiram, ethanol and the association disulfiram-ethanol on gastro-intestinal motility and ethanol absorption was studied in rats. It was observed that disulfiram (25 mg/kg) and ethanol (0,8 g/kg), separately administered, decrease gastric emptying a nd increase propulsion in the small intestine; association of the two treatments results in the addition of the particular effects, except in the first intestinal segment. Disulfiram reduces ethanol absorption; very significant correlations have been noted between gastric emptying and ethanol absorption.


[Fat embolism. A new therapeutic approach to ligation of the inferior vena cava]. An analys is made of the frequency of fat-embolism in patients with battle wounds and in those who suffer traumatisms in every day life; it was found in a high percentage in both groups. It is noted that when tye symptom appear little after the traumatism, the percentage of death is higher (85%) than when they appear within 24 to 72 hours later (10-20%). During 5 year, in the Hospital Central Militar de Mexico 12 cases of fat-embolism have been diagnosed. The first ten were handled by the classic method: ventilatory assistance, corticoids, heparin, etc.; having 30% of deaths. The two last ones were treated by ligation of the inferior vena cava; none of the two died and there was a remarkable change in the course of the clinical manifestations. Based on the experience of the group, in more than 120 cases with ligation of the inferior vena cava due to pulmonary thromboembolism; there was a symptomatic paralelism found between the fat-embolia and the repeated venous embolism; and in our opinion we conclude that the progressiveness of the respiratory insufficiency is due to repeated fat-emboly more so than to the convertion of neutral fat into fatty acids through the action of lipasa in various tissues. With this hypothesis the inferior vena cava was ligated in two patients, and the results obtained were the ones mentioned before. It is emphasized that the procedure has a very low risk of death and there are minimum sequels, more in relationship to the previous flebitic state, than to the ligation itself. It is indicated that the corticosteroids, heparin, ventilatory and cardiac assistance be continued, besides elastic bandage, elevation of the pelvic limbs, exercises, etc. It is accepted that two cases cannot be enough to fully demonstrate how good the method is, but the changes of progress of these two cases after the ligation were so notable, that we are able to recommend this method in all those patients with an important fat-embolism. It is indicated that in the laboratory of Experimental Surgery of the H.C.M. experiments are being made to demonstrate what has been obtained clinically.


Effects of quinidine and diphenylhydantoin on membrane resistance in smooth muscle. The effects of quinidine and diphenylhydantoin on the membrane electrical resistance of guinea-pig taenia coli have been studied by means of the double sucrose gap tachnique. At concentrations ranging from 2 to 7.10-minus 5 quinidine induces an evident dose-related increase of membrane resistance, as indicated by the increase of the electrotonic potential. These effects are unaffected by tetrodotoxin (10(-6)) and in the presence of various changes of ionic environment (replacement of Na by Li, increase of K or Ca or Mg concentrations). Only a concomitant rise of both K and Ca (or Mg) can prevent the effects of quinidine on membrane resistance. The rate of repetitive discharge under sustained electrical depolarization is not affected by quinidine, at concentrations increasing membrane resistance. The experiments with diphenylhydantoin showed that this drug is practically ineffective on membrane resistance, but induces a decrease of the rate of repetitive discharge under sustained depolarization.


Drugs and punished responding. V.  Effects of drugs on responding suppressed by response-dependent and response-independent electric shock. A procedure was used where responses by a pigeon produced electric shock both to that pigeon (response-dependent shock) and to another pigeon (response-independent shock) working under the same schedule of food presentation. Both response-dependent and response-independent shock partially suppressed responding. Pentobarbital, chlordiazepoxide and ethanol increased responding suppressed by response-dependent shock, but only pentobarbital increased responding suppressed by response-independent shock. Morphine, d-amphetamine, chlorpromazine, doxepin, and pentazocine either had no effect, or further decreased rates of responding suppressed by response-dependent or response-independent shock.


[Pulmonary complications of acute myocardial infarct. Therapeutic orientation]. The heart and the lung make up an inseparable anatomic and functional unit. The changes in one affect the other and vice versa. In acute myocardial infarction a heart failure syndrome develops. This syndrome is characterized by passive pulmonary congestion, which leads to hypoxemia. This hypoxemia indicate the functional disturbance of the lung, and the hemodinamic evolution of the disease. Arterial gases determination is the best way to assess the sickness progression. A certain paralelism exists among the central venous saturation, cardiac insufficiency and the degree of pulmonary disfunction. Such a procedure is not very appreciable and does not substitute the direct analysis of the arterial PO2. The pulmonary complications in the myocardial infarction shock are directly responsable of death in 50% of the patients. To heart failure and shock, hipperfusion and hypoxia are added. Many vessels close due to the decrease in the pulmonary flow. This brings about the release of substances that are toxic to the vessel causing an inflammatory vascular reaction. The decrease in the flow harms the lung cell and for this reason atelectasia or alveolar colapse occur; besides inducing the formation of shunts. Under these conditions the lung compliance decreases. The areas that are badly ventilated and hypoperfused can easily become infected and pneumonitis and abscesses cause even more harm to the tissue. The decrease in the speed of circulation and hematologic changes of shock, induce a diseminated intravascular coagulation. What was stated before leads to an important reduction of the lung as a depurating organ and makes the shock irreversible. As far as therapy is concerned in the prevention of vascular colaps and the improvement of the oxemia, oxygen is very useful when there is a venous congestion (clinically, X rays, and oxemia). When the concentration of O2 is lower than 50% in the cases with slight cardiac failure; do not use oxygen in higher concentrations unless the hypoxia is associated to acute pulmonary edema and shock. Mechanic ventilators, and intermitent possitive pressure are recommended even though they have a posenous effect on the cardiac output. Always keep the air ways permeable: changing position, breathing exercises, humidifications, aspiration of secretions, intubation, or traqueostomy depending upon the various cases.


General pharmacology of a new analgesic-AP-237. 1-n-Butyryl-4-cinnamylpiperazine hydrochloride, AP-237, was studied in a variety of general screening tests. Several routes of administration, including oral, subcutaneous, intraperitoneal, and intra-muscular, were employed. It was compared to morphine and pentazocine in many tests. It was found to be a potent analgesic in rats and mice with better oral efficacy than the reference agents. It did not exhibit anti-inflammatory, antipyretic, or anticonvulsant activity but appeared to have some tranquilizing properties. Its general pharmacology resembles the reference agents morphine and pentazocine, but with several differences.


[Aneurysm of the left ventricle associated with inactive rheumatic heart disease. Report of a case]. A case of aneurism of the left ventricle, confirmed by ventriculogram, associated to an inactive rheumatic cardiopathy with a pure mitral stenosis is presented. Since none of the usual causes that have been reported were found to explain the aneurism of the left ventricle; the possibility of the aneurism resulting from residual myocardiac fibrosis produced by the rheumatic myocarditis is suggested.


Effects of vasodilating agents on the microcirculation in marginal parts of the skeletal muscle. The present investigation was performed to gain information on the changes in the microcirculation of the skeletal muscle during the application of vasodilating agents. The flow velocity in various microvessels was measured cinematographically in isolated and non-isolated muscles of the hindlimb in cats and rats. During the intra-arterial infusion of acetylcholine (1 mug/kg times min), bradykinin (2 mug/kg times min) and isoprenaline (1 mug/kg times min) a decrease in the flow velocity up to a complete stasis was found in most of the microvessels in the marginal parts of the muscles examined. These reactions set in when the femoral flow increased and disappeared when the femoral blood flow returned to the baseline level. The experiments demonstrate that the increase in total blood flow induced by the intra-arterial infusion of vasodilating agents may be associated with a reduced perfusion of certain parts of the striated muscles.


Analgesic and tolerance studies with AP-237, a new analgesic. 1-n-Butyryl-4-cinnamylpiperazine hydrochloride, AP-237, is a new analgesic that has been reported in both Japan and the United States to have good analgesic activity in animals and is currently undergoing clinical trials. A detailed study of the analgesic and side effect profile of this compound is presented. AP-237 was an effective analgesic in a variety of species by several different routes of administration. Results of studies in an inflamed paw pressure and tail flick test in rats, hot plate and writhing test in mice, tooth pulp test in rabbits and intra-arterial bradykinin test in dogs are reported. AP-237 had a low physical dependence liability in rodents as measured by a mouse jumping test and a lack of withdrawal syndrom. Tolerance and cross tolerance results are reported. AP-237 is compared to morphine and pentazocine in most tests.


Correlation between brain monoamine levels and postictal coma following electroshock. Duration of postictal coma following maximal electroshock seizure and monoamine levels in the whole brain were measured in mice. Pretreatment with intraperitoneal alpha-methyl-p-tyrosine (alpha-MT), 5-hydroxytryptophane (5-HTP), or intraventricular 6-hydroxydopamine (6-OHDA) prolonged the coma duration, whereas p-chlorophenylalanine (PCPA) did not affect the coma, and L-DOPA tended to shorten the coma and counteracted the effect of alpha-MT. When the shock was repeated five times with one hour intervals, the duration of coma was progressively increased being accompanied by elevated serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) levels in the brain. In alpha-MT treated group, a striking parallelism was remarked between coma prolongation and norepinephrine (NE) or dopamine (DA) reduction. These data suggest that prolongation of postictal coma is correlated with reduced NE and DA levels and/or with elevated 5-HT and 5-HIAA levels in the brain.


Effects of taclamine (AY-22,214), a new psychoactive agent, on catecholamine and serotonin metabolism. The effects of a new psychopharmacologically-active agent taclamine (AY-22,214 (AY)(a dibenzocycloheptaisoquinolines)) on noradrenaline (NA), dopamine (DA) and serotonin(5-HT) turnover in the brains of normal and/or stressed animals were determined by the use of both non-isotopic and isotopic techniques; a comparison with chlordiazepoxide (CL) was carried out. Both AY and CL antagonized the increase in NA and 3H-NA turnover due to immobilization stress in whole, and selected regions, of the rat brain. AY, unlike CL did not decrease 3H-NA turnover in brains of non-stressed animals. AY accelerated the turnover of DA in whole brain and 3H-DA in the striatum. In contrast, CL decreased turnover of each. AY did not alter 5-HT turnover. CL decreased 14C-5-HT turnover in regions of rat brain; in addition, it antagonized the pargyline-induced rise in 5-HT and potentiated the subsequent fall in levels of 5-HIAA. Neither AY nor CL affected the 5-HT uptake in the mouse brain. It  is concluded that AY appears to exhibit both similarities and differences to CL with regard to its effects on biogenic amine turnover.


Tolerance development to the effect of delta9-tetrahydrocannabinol on conditioned behavior: role of treatment interval and influence of microsomal metabolism. The importance of frequency of administration in the development of tolerance to delta9-tetrahydrocannabinol (delta9-THC) was studied with repeated administration of the drug prior to behavioral test sessions at 1-, 3-, 7- or 14-day intervals. Partial tolerance was seen to develop to the depressant effects of delta9-THC (10mg/kg i.p.) on food-motivated performance on a variable interval 60-sec (VI 60) schedule of reinforcement. The tolerance was most evident with the most frequent exposure to the drug. No signs of increasing responsiveness to delta9-THC were seen with any of the four inter-injection intervals. The role of hepatic metabolism in tolerance to delta9-THC was tested by pretreating animals with SKF-525A, a microsomal enzyme inhibitor, or phenobarbital, a microsomal enzyme inducer. The dosing schedules for SKF-525A and phenobarbital were sufficient to alter hexobarbital sleeping time significantly, but they did not affect the normal VI 60 sec performance. After a 5 mg/kg dose of SKF-525A the depressant actions of 3 and 10 mg/kg doses of delta9-THC appeared to show a slight but consistent enhancement during the course of tolerance development. Phenobarbital (80 mg/kg/day) pretreatment for seven days blocked the acute behavioral depressant effect of 3 mg/kg of delta9-THC and appeared to enhance the development of tolerance. A metabolic mechanism of tolerance development was suggested by the data, but not demonstrated definitively.


Interaction between centrally acting hypotensive drugs and tricyclic antidepressants. From clinical experience it is known that the hypotensive action of clonidine and alpha-methyl-DOPA is antagonized by desipramine. This antagonism was investigated in detail in chloralose-anaesthetized cats. Both the centrally acting hypotensive agents and the tricyclic antidepressants where infused into the left vertebral artery. (1) The central hypotensive action clonidine was antagonized by desipramine, imipramine, amitriptyline, protriptyline and mianserine. For the inhibition of the hypotensive action of clonidine by protriptyline a parallel shift of the dose-response curve was obtained, indicating the possibility of a competitive antagonism. The central hypotensive action of alpha-methyl-DOPA was antagonized by desipramine and imipramine and that of amphetamine by imipramine. (2) The modest central hypotensive action of tricyclic antidepressants themselves and that of cocaine is explained by means of the inhibition of noradrenaline re-uptake in the CNS, brought about by these compounds. (3) It seems likely that the antagonism occurs at the level of central alpha-adrenoreceptors in the brain stem. (4) The antagonism probably reflects a general interaction between centrally acting hypotensive drugs and tricylclic antidepressants. The alpha-sympatholytic properties of the tricyclic antidepressants probably give rise to a blockade of the central alpha-adrenoreceptors, stimulated by clonidine, noradrenaline (via amphetamine) and alpha-methylnoradrenaline (from alpha-methyl-DOPA). The cocaine-like activity of antidepressants does not play a part.


Pharmacodynamic distinctions between ouabain, digoxin and digitoxin. Current pharmacologic texts recognize no significant pharmacodynamic differences between the various cardiac glycosides. To reconsider this concept, a special recording device was constructed so that electrocardiograms and phonocardiograms could be obtained in small mammals without anesthesia or premedication, and a spectrum of cardiac glycosides was studied. Utilizing guinea-pigs, cardiac rate reduction of 20% was sought and achieved with 0.07 mg/kg ouabain, 0.34 mg/kg digoxin and 1.12 mg/kg digitoxin. With comparable rate reduction, digitoxin produced significantly greater shortening of electro-mechanical systole than did ouabain or digoxin (P less than 0.05). Other authors have shown that cardiac glycosides produce slowing of cardiac rate prior to onset of positive inotropic effect. Therefore it is probable that for a given amount of vagal effect (sinoatrial slowing) digitoxin possesses greater positive inotropic effect (abbreviation of electromechanical systole) in guinea-pigs than do ouabain or digoxin. A review of the literature suggests that the same holds true for humans.


The action of clonidine on the baroreflex control of heart rate in conscious animals and man, and on single aortic baroreceptor discharge in the rabbit. Changes in mean arterial pressure (M.A.P.) have been produced in conscious rabbits by inflation of balloon cuffs previously implanted round the inferior vena cave and aorta; Sigmoid stimulus/response curves (M.A.P./Heart Period, H.P.) were constructed. Clonidine caused a striking dose dependent increase in gain of the reflex arc in both normal rabbits and rabbits with renal hypertension. The largest effect was upon vagal motorneurones but a similar but smaller effect was present in vagotomised animals. Similar changes in the baro-reflex arc were produced by injection of very much smaller doses of clonidine into the lateral cerebral ventricle. Recordings made from single aortic baroreceptor fibres in anaesthetised rabbits showed again a dose dependeent sensitisation. These results suggest that the bradycardia caused by clonidine is largely mediated via an action in the brain on the baroreflex arc, with an additional action on the baroreceptors themselves. Preliminary results in normal man show a similar increase in the gain of this reflex after intravenous clonidine (150 mug).


Uptake and release of 3-H-metaraminol by rat lung. Basic aspects, ionic and energy requirements. The accumulation of 3H-metaraminol in incubated lung tissue of the rat was examined in vitro. Lung tissue concentrated tritium after incubation with 3H-metaraminol. This uptake proceeds against a concentration gradient and shows saturation kinetics (Km 12.5 X 10(-7) M and Vmax 2.105 nM/g/15 min.) with great affinity for 3H-metaraminol. The accumulation of 3H-metaraminol is dependent of temperature and energy supply, and requires the presence of sodium ions. The loss of accumulated radioactivity showed the possibility that a small fraction of metaraminol is apparently firmly boune (e.g. neuronal sites), while a greater portion is taken up by extraneuronal structures (e.g. capillary endothelial cells). The first localization could represent uptake-1 and the second uptake-2. The results obtained also confirm the important role of the lungs as an organ which participates in the fate of endogenous substances and drugs.


Evaluation of ketamine HCl for anti-depressant activity. Using several routine screening procedures to determine anti-depressant drug activity in experimental laboratory animals, ketamine HCl was found to possess significant activity over a wide-range of oral doses. The tests used were (a) reversal of tetrabenazine-induced ptosis in mice, (b) reversal of reserpine-induced hypothermia in rats, (c) enhancement of yohimbine toxicity in mice and (d) inhibition of oxotremorine-induced tremors in mice. In general, the anti-depressant potency of ketamine HCl was substantially less than that of imipramine HCl.


Etomidate, a potent non-barbiturate hypnotic. Intravenous etomidate in mice, rats, guinea-pigs, rabbits and dogs. Etomidate, R-(+)-ethyl-1-(1-phenylethyl)-1H-imidazole-5-carboxylate was found to be a potent, short-acting and safe hypnotic; when given intravenously in single doses to mice, rats, guinea-pigs, rabbits and dogs. In rats of different body weight (50, 100, 200 and 300 g) two injection rates were used (2 sec and 2 min). By rapid iv injection in rats of 200 g etomidate (ED50 equal to 0.57 mg/kg) is about 6 times more potent than methohexital (ED50 equal to 3.51 mg/kg) and 25 times more potent than propanidid and thiopental (ED50's equal to 13.4 mg/kg). The safety margin (LD50/ED50) in these rats is 26.0 for etomidate, 9.5 for methohexital, 6.7 for propanidid and 4.6 for thiopental. Potency and toxicity of etomidate slightly increase with increasing injection rates without affecting the safety margin. The duration of hypnosis with etomidate is dose-dependent and the safety margin will therefore be widened when sleep of short duration is aimed at. Recovery after etomidate is very rapid. With lower body weights, higher doses in mg/kg are required for inducing hypnosis of comparable duration. No systematic differences were found after etomidate injection in incidence and duration of hypnosis nor in mortality between animals of different sex. ECG, blood pressure, haematological and biochemical analysis, urinalysis and histopathology did not reveal any drug-related adverse effect after daily injection of etomidate for 3 weeks in rats (highest dose 5.0 mg/kg) and 2 weeks in dogs (highest dose 1.50 mg/kg). No tolerance was observed after repeated administration. Etomidate is devoid of any teratogenic effect in rats (highest dose: 5.0 mg/kg daily from day 6 through day 15 of pregnancy), and in New Zealand white rabbits (highest dose: 4.5 mg/kg daily from day 6 through day 18 of pregnancy). The hypnotic effects of etomidate at very low dose levels in different laboratory animals are compared with the effects obtained in human subjects, in which successful induction of anaesthesia was obtained without producing any release of histamine and with only minimal effects on cardiovascular and respiratory functions.


Age-dependent cardiovascular effects of halothane anesthesia in neonatal pigs. The cardiovascular effects of halothane anesthesia in a mixture of nitrous oxide and oxygen were studied on piglets 7 hr to 25 days of age. Blood pressure, heart rate and peripheral flows were recorded simultaneously in all animals. Body temperature and blood gas composition and pH were monitored and maintained within normal physiological limits for piglets. Inspired halothane concentration was kept at 1.0% during vascular surgery and then increased or decreased systematically. Halothane anesthesia depressed mean aortic pressure and increased carotid, femoral and renal resistances in piglets less than one week of age. These effects increased with increasing halothame concentrations from 0.25% to 1.5%. In older animals, mean aortic pressure changes were significant only at halothane concentrations above 1.0%, while peripheral resistances were unaffected. Although there was no concentration-dependent change in heart rate in either age group, heart rates were consistenly faster in younger animals.


Electrophysiological evidence for an inhibitory action of diazepam upon cat brain cortex. Diazepam was shown to increase postexcitatory inhibition within the brain cortex as revealed by its influence upon the recovery cycles both of intracortical and primary responses. The specific interrelationship between diazepam and some drugs affecting brain GABA level suggests the possibility of a GABA mediated mechanism in the diazepam effect. The sensitivity of the brain cortex to diazepam is not lower than that of the amygdala and significantly higher than that of the hippocampus.


Interaction between aluminum and calcium ions in potassium chloride depolarized gastrointestinal smooth muscle. Aluminum chloride (5 times 10-minus 4 M) abolished the inhibitory effects of papaverine chloride (1.5 times 10- minus 5 M) on contractions of guinea-pig ileum and rat colon evoked by calcium in Tyrode's solution containing high KC1. The inhibitory effects of cocaine hydrochloride (10- minus 3 M) and MgSO4 (2 times 10- minus 2 M) were not antagonized. In isolated rat colon depolarized by partial exchange of NaCl by 40 mM KC1, AlC13 decreased the phasic contractions, slowed the onset of tonic contraction while increasing maximal tone and induced superimposed spontaneous activity during the tonic phase. Similar changes were evoked by increasing the CaCl2 concentration from 1.8 times 10- minus 3 M to 7.2 times 10- minus 3 M. The increase in spontaneous activity was not blocked by atropine sulfate (10- minus 7 minus 10- minus 4 M) but was partially antagonized by 10- minus 3 M caffeine and completely blocked by papaverine chloride (5 times 10- minus 4 M). More than one aluminum site of action is proposed for effects of aluminum on the gastro-intestinal smooth muscle.


On the problem of a common hepatic transport process for steroids. Uptake of 3-H-taurocholic acid and 3-H-corticosterone into rat liver slices. The uptake of 3-H-oubain (2 times 10- minus 9 and 2 times 10- minus 5 M), 3-H-taurocholic acid (2 times 10- minus 8 and 2 times 10- minus M) and 3-H-corticosterone (2 times 10- minus 9 and 2 times 10- minus 5M) into rat liver slices was investiged. The steroids were extensively accumulated as demonstrated by the following T/M ratios: ouabain: 3.82 and 3.72 resp.; taurocholic acid: 10.49 and 9.88 resp.; corticosterone: 12.84 and 8.41 resp.. Only corticosterone uptake was dependent on the medium concentration but without alterations under anaerobic conditions. The contrary could be found in case of ouabain and taurocholic acid. Further differences between the steroids investigated could be shown in experiments on the interaction with organic anions (probenecid, para-aminohippuric acid, citrate and alpha-ketoglutarate). At least no competition among the steroids concerning their uptake into liver tissue could be demonstrated. The results are discussed in contradiction to the current theories concerning the hepatic uptake of steroid compounds.


Antiinflammatory activity of alpha-methyl-3-phenyl-7-benzofuranacetic acid (R-803). The antiinflammatory activity of R-803 (alpha-methyl-3-phenyl-7-benzofuranacetic acid), a new nonsteroidal drug, has been demonstrated. The oral administration of R-803 inhibits carrageenan-induced edema of the rat's paw, ultraviolet-induced erythema of guinea-pig skin, adjuvant-induced and 6-sulfonamidoindazole-induced arthritides of the rat at doses in the range of 1.0 to 6.0 mg/kg. It also inhibits the cotton pellet-induced granuloma in the rat at higher doses.


Blockade of the stimulus properties of mescaline by a serotonin antagonist. It is known that the effects of mescaline (3, 4, 5-trimethoxyphenylethylamine), a hallucinogen, can function as a discriminative stimulus. The present investigation examined the ability of cinanserin, a serotinin antagonist, to block the stimulus properties of mescaline in the rat. After a reliable discrimination was established between the effects following the injection of mescaline (10 mg/kg) and those following administration of saline, subjects were pretreated with cinanserin HC1 (3 mg/kg) and then treated with mescaline. Such pretreatment was found to block discrimination, i.e., the response rate following the administration of mescaline plus cinanserin was appropriate for the saline condition. The present data suggest that antagonists of serotonin may be useful in furthering our understanding of phenethylamine hallucinogens.


Biochemical pharmacology of some chlorinated 3-phenyl-piperidines in rats. Chlorinated 3-phenyl-piperidines were administered to rats with the expectation--based on structural similarities--that they might resemble chlorinated amphetamines pharmacologically. The 3-chloro, 4-chloro, and 3,4-dichloro compounds all lowered serotonin and 5-hydroxyindoleacetic acid levels in rat brain, whereas the 2-chloro compound had no effect. The brain levels and half-lives of the four compounds suggested that the compounds might be metabolized by hydroxylation at the 4- position of the phenyl ring. Desmethylimipramine, an inhibitor of amphetamine hydroxylation in the 4- position, markedly elevated brain levels of the 2-chloro compound and to a lesser extent of the 3-chloro compound. The 2-chloro compound did not lower brain serotonin levels even in desmethylimipramine-treated rats, however. The results suggest that some pharmacologic properties of the chlorinated 3-phenyl-piperidines are indeed similar to those of chlorinated amphetamines.


The effect of methyl paraben on tracheal smooth muscle in vitro. The widely used bacteriostatic preservative methyl paraben (M.P.) produced a concentration-dependent relaxation of the carbachol-contracted guinea pig trachea and the isolated rabbit jejunum. The relaxant effects on the trachea were not blocked by dl-propranolol and the responses on the rabbit jejunum were not blocked by bretylium tosylate which abolished the responses to sympathetic nerve stimulation. Sub-threshold concentrations of M.P. (130 muM) produced a marked and significant enhancement of the responses of the trachea to the three catecholamines dl-isoprenaline (I), 1-noradrenaline (N), 1-adrenaline (A), a slight but significant enhancement of the responses of the trachea to the two non-catechol beta sympathomimetics salbutamol (S), and orciprenaline (O), but no significant enhancement of the responses to aminophylline (AM). It is concluded that the relaxant effect of M.P. is characteristic of a "non-specific" spasmolytic and this is consistent with its reported local anaesthetic activity. In addition, the specific ability of M.P. to enhance responses to catecholamines suggests that it may be interacting with a mechanism responsible for catecholamine removal (i.e., tissue uptake or uptake 2). In view of the widespread use of M.P. in pharmaceutical preparations in concentrations often equivalent to or greater than those employed in the present investigation, the fact should be stressed that its presence should not be overlooked in the interpretation of experimental and clinical studies.


The effects of 5-hydroxy-5(4'-chlorophenyl)-2, 3-dihydro-5H-imidazo (2, 1-a) isoindole (mazindol, SaH 42-548) on the metabolism of brain norepinephrine. Mazindol, 5-hydroxy-5-(4'-chlorophenyl)-i, 3-dihydro-5H-imidazo-(2, 1-a) isoindole, has demonstrated anorexic activity and other pharmacological responses which suggest alterations in brain norepinephrine metabolism. Studies of the effects of mazindol on neuronal uptake and/or release of norepinephrine showed that mazindol, when given before cerebral intraventricular injection of 3-H-norepinephrine by a mechanism that increases 3-H-normetanephrine synthesis via catechol-O-methyl-transferase and provided no significant effect on deamination of the catecholamine. Studies designed to measure norepinephrine release showed that mazindol (in contrast to d-amphetamine) did not cause release of 3-H-norepinephrine from neuronal stores. Furthermore, mazindol did not inhibit norepinephrine synthesis, whereas d-amphetamine did. The effect of d-amphetamine on norepinephrine release and synthesis may be more important than effects on uptake of this catecholamine. In contrast, mazindol appears to produce its primary effect on norepinephrine metabolism by inhibition of neuronal uptake mechanism.


Increase of experimental hypertension following inhibition of prostaglandin biosynthesis. To demonstrate the role of endogenous renal prostaglandins as modulators of the renin-angiotensin-system in renal hypertension, rats with acute and chronic renal hypertension were pretreated with different inhibitors of the prostaglandin biosynthesis (indomethacin, mefenamic acid, acetylsalicylic acid. Development and course of acute and chronic renal hypertension after treatment were highly significantly different from untreated animals concerning elevation, duration and intensity of renal hypertension. Moreover, indomethacin enhanced renal vasoconstrictor effect of angiotensin II in the dog; accordingly, inhibition of prostaglandin biosynthesis increases acute and chronic renal hypertension. It seems that prostaglandins play an important part in blood pressure regulation.